Structure–activity relationship of insulinomimetic vanadyl–picolinate complexes in view of their clinical use

<jats:title>Abstract</jats:title><jats:p>In view of the clinical use of vanadium compounds, we prepared seven analogs of a vanadyl–picolinate complex (VO(pic)<jats:sub>2</jats:sub>) with VO(N<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>) coordination mode, which was found in 1995 to exhibit highly effective and long‐term insulinomimetic activity in treating both streptozotocin (STZ)‐induced type 1 diabetic rats (STZ rats) and hereditarily type 2 diabetic KK‐A<jats:sup>y</jats:sup> mice by daily intraperitoneal (i.p.) injections and on oral administration, to find the structure–activity relationship of the complexes. Using an in vitro insulinomimetic evaluation of the complexes in terms of their inhibiting effect on free fatty acids release from isolated rat adipocytes treated with epinephrine (adrenaline), we found the activity (IC<jats:sub>50</jats:sub>: 50% inhibitor's concentration of the complex on the free fatty acid release) to be as follows: VO(5ipa)<jats:sub>2</jats:sub> > VO(3mpa)<jats:sub>2</jats:sub> > VO(6mpa)<jats:sub>2</jats:sub> > VO(3hpa)<jats:sub>2</jats:sub> > VO(pic)<jats:sub>2</jats:sub> > VO(6hpa)<jats:sub>2</jats:sub> ≈ VOSO<jats:sub>4</jats:sub>, indicating that the introduction of an electron‐withdrawing halogen atom or an electron‐donating methyl group at the 5th or 3rd position on the picolinate ligand causes stronger insulinomimetic activity than that of the lead complex VO(pic)<jats:sub>2</jats:sub>. Next we examined the pharmacokinetic features in the blood of the complexes by using the blood circulation‐monitoring electron spin resonance method, in which good linear relationships between the pharmacokinetic parameters and the IC<jats:sub>50</jats:sub> values were found. Based on the results, we tested the complexes and found that both VO(5ipa)<jats:sub>2</jats:sub> and VO(3mpa)<jats:sub>2</jats:sub> complexes treat type 1 diabetes in STZ rats. Because the daily oral administration of vanadyl complexes is the only method to treat type 1 diabetes in place of daily insulin injections, the present results will be useful for the development of vanadyl complexes with high safety and long‐term activity. J. Trace Elem. Exp. Med. 16:269–280, 2003. © 2003 Wiley‐Liss, Inc.</jats:p>